Treatment of experimental autoimmune encephalomyelitis (EAE) mice with the estrogen receptor (ER) β ligand diarylpropionitrile (DPN) has been shown to have neuroprotective effects via stimulation of ...endogenous myelination. The direct cellular mechanisms underlying the effects of this ERβ ligand on the central nervous system are uncertain because different cell types in both the peripheral immune system and central nervous system express ERs. ERβ is the target molecule of DPN because DPN treatment fails to decrease EAE clinical symptoms in global ERβ-null mice. Here we investigated the potential role of ERβ expression in cells of oligodendrocyte (OL) lineage in ERβ ligand-mediated neuroprotection. To this end, we selectively deleted ERβ in OLs using the well-characterized Cre-loxP system for conditional gene knockout (CKO) in mice. The effects of this ERβ CKO on ERβ ligand-mediated neuroprotective effects in chronic EAE mice were investigated. ERβ CKO in OLs prevented DPN-induced decrease in EAE clinical disease. DPN treatment during EAE did not attenuate demyelination, only partially improved axon conduction, and did not activate the phosphatidylinositol 3-kinase/serine-threonine-specific protein kinase/mammalian target of rapamycin signaling pathway in ERβ CKO mice. However, DPN treatment significantly increased brain-derived neurotrophic factor levels in ERβ CKO mice. These findings demonstrate that signaling through ERβ in OLs is essential for the beneficial myelination effects of the ERβ ligand DPN in chronic EAE mice. Further, these findings have important implications for neuroprotective therapies that directly target OL survival and myelination.
Background: The WHO recently has recommended the GenoType MTBDRplus version 1.0 and MTBDRsl version 1.0 assays for widespread use in countries endemic with drug-resistant tuberculosis. Despite this, ...these assays have rarely been evaluated in China, where the burden of drug-resistant tuberculosis is among the highest globally. Methods: Mycobacterium tuberculosis clinical isolates were obtained between January 2008 and December 2008. Isolates were tested for drug resistance against rifampicin (RFP) and isoniazid (INH) using the GenoType MTBDRplus assay and drug resistance against ethambutol (EMB), ofloxacin (OFX), and kanamycin (KM) using the Genotype MTBDRsl assay. These results were compared with conventional drug-susceptibility testing (DST). Results: Readable results were obtained from 235 strains by GenoType MTBDRplus assay. Compared to DST, the sensitivity of GenoType MTBDRplus assay to detect RFP, INH, and multidrug resistance was 97.7%, 69.9%, and 69.8%, respectively, whereas the specificity for detecting RFP, INH, and multidrug resistance was 66.7%, 69.2%, and 76.8%, respectively. The sensitivity and specificity of the GenoType MTBDRsl assay were 90.9% and 95.2% for OFX, 77.8% and 99.5% for KM, 63.7% and 86.4% for EMB, respectively. Mutations in codon S531L of the rpoB gene and codon S315T1 of KatG gene were dominated in multidrug-resistant tuberculosis (MDR-TB) strains. Conclusions: In combination with DST, application of the GenoType MTBDRplus and MTBDRsl assays may be a useful supplementary tool to allow a rapid and safe diagnosis of multidrug resistance and extensively drug-resistant tuberculosis.
•Only PHAs were aerobically/anaerobically biodegradable under aqueous conditions.•PHB and PHBV yielded up to 496 and 480 Nm3 of CH4 per ton, respectively.•C-balance analysis for the different carbon ...sinks estimates polymer biodegradability.•Mineralization rate depended on the total specific surface area of polymer.•The modified Gompertz model accurately described bioplastic biodegradation.
The biodegradation of PHB, PHBV, PBS, PBAT, PCL, PLA, and a PLA-PCL blend was compared under aerobic and anaerobic aqueous conditions assessing biodegradation kinetics, extent, carbon fate and particle size influence (in the range of 100–1000 µm). Under standard test conditions, PHB and PBHV were biodegraded anaerobically (83.9 ± 1.3% and 81.2 ± 1.7%, respectively) in 77 days or aerobically (83.0 ± 1.6% and 87.4 ± 7.5%) in 117 days, while PCL was only biodegraded (77.6 ± 2.4%) aerobically in 177 days. Apparent biomass growth accounted for 10 to 30.5% of the total initial carbon depending on the bioplastic and condition. Maximum aerobic and anaerobic biodegradation rates were improved up to 331 and 405%, respectively, at the lowest particle size tested (100–250 µm). This study highlights the usefulness of analysing biodegradation kinetics and carbon fate to improve both the development and testing of biodegradable materials, and waste treatments in the context of a circular bioeconomy.
Background： The WHO recently has recommended the GenoType MTBDRph/s version 1.0 and MTBDRs/version 1.0 assays for widespread use in countries endemic with drug-resistant tuberculosis. Despite this, ...these assays have rarely been evaluated in China, where the burden of drug-resistant tuberculosis is among the highest globally. Methods： Mycobacterium tuberculosis clinical isolates were obtained between January 2008 and December 2008. Isolates were tested for drug resistance against rifampicin （RFP） and isoniazid （INH） using the GenoType MTBDRplus assay and drug resistance against ethambutol （EMB）, ofloxacin （OFX）, and kanamycin （KM） using the Genotype MTBDILsl assay. These results were compared with conventional drug-susceptibility testing （DST）. Results： Readable results were obtained from 235 strains by GenoType MTBDRphts assay. Compared to DST, the sensitivity of GenoType MTBDRplus assay to detect RFP, INH, and multidrug resistance was 97.7%, 69.9%, and 69.8%, respectively, whereas the specificity for detecting RFP, INH, and multidrug resistance was 66.7%, 69.2%, and 76.8%, respectively. The sensitivity and specificity of the GenoType MTBDRsl assay were 90.9% and 95.2% for OFX, 77.8% and 99.5% for KM, 63.7% and 86.4% for EMB, respectively. Mutations in codon S531L of the rpoB gene and codon S315T1 ofKatG gene were dominated in multidrug-resistant tuberculosis （MDR-TB） strains. Conclusions： In combination with DST, application of the GenoType MTBDRplus and MTBDRsl assays may be a useful supplementary tool to allow a rapid and sale diagnosis of multidrug resistance and extensively drug-resistant tuberculosis.
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•Lactate-based H2-fermentation systems are extensively reviewed.•Substrate features, culture conditions and biological factors are discussed in detail.•Lactate-to-H2 route is ...promising to deal with lactate producers’ over-proliferation.•The proposed approach can be applied for cheese whey, food waste, vinasse and others.•Balanced microbial equilibrium required to maintain acceptable hydrogen productivity.
Dark fermentation (DF) is one of the most promising biological methods to produce bio-hydrogen and other value added bio-products from carbohydrate-rich wastes and wastewater. However, process instability and low hydrogen production yields and rates have been highlighted as the major bottlenecks preventing further development. Numerous studies have associated such concerns with the inhibitory activity of lactate-producing bacteria (LAB) against hydrogen producers. However, an increasing number of studies have also shown lactate-based metabolic pathways as the prevailing platform for hydrogen production. This opens a vast potential to develop new strategies to deal with the “Achilles heel” of DF – LAB overgrowth – while untapping high-performance DF. This review discusses the key factors influencing the lactate-driven hydrogen production, paying particular attention to substrate composition, the operating conditions, as well as the microbiota involved in the process and its potential functionality and related biochemical routes. The current limitations and future perspectives in the field are also presented.
World Health Organization recommends countries introducing new drug and short treatment regimen for drug resistant tuberculosis (DR-TB) should develop and implement a system for active ...pharmacovigilance that allows for detection, reporting and management of adverse events. The aim of the study is to evaluate the frequency and severity of adverse events (AEs) of bedaquiline-containing regimen in a cohort of Chinese patients with multidrug-resistant (MDR)/extensively drug-resistant (XDR)-TB based on active drug safety monitoring (aDSM) system of New Drug Introduction and Protection Program (NDIP).
AEs were prospectively collected with demographic, bacteriological, radiological and clinical data from 54 sites throughout China at patient enrollment and during treatment between February, 2018 and December, 2019. This is an interim analysis including patients who are still on treatment and those that have completed treatment. A descriptive analysis was performed on the patients evaluated in the cohort.
By December 31, 2019, a total of 1162 patients received bedaquiline-containing anti-TB treatment. Overall, 1563 AEs were reported, 66.9% were classified as minor (Grade 1-2) and 33.1% as serious (Grade 3-5). The median duration of bedaquiline treatment was 167.0 interquartile range (IQR): 75-169 days. 86 (7.4%) patients received 36-week prolonged treatment with bedaquiline. The incidence of AEs and serious AEs was 47.1% and 7.8%, respectively. The most frequently reported AEs were QT prolongation (24.7%) and hepatotoxicity (16.4%). There were 14 (1.2%) AEs leading to death. Out of patients with available corrected QT interval by Fridericia's formula (QTcF) data, 3.1% (32/1044) experienced a post-baseline QTcF ≥ 500 ms, and 15.7% (132/839) had at least one change of QTcF ≥ 60 ms from baseline. 49 (4.2%) patients had QT prolonged AEs leading to bedaquiline withdrawal. One hundred and ninety patients reported 361 AEs with hepatotoxicity ranking the second with high occurrence. Thirty-four patients reported 43 AEs of hepatic injury referred to bedaquiline, much lower than that referred to protionamide, pyrazinamide and para-aminosalicylic acid individually.
Bedaquiline was generally well-tolerated with few safety concerns in this clinical patient population without any new safety signal identified. The mortality rate was generally low. These data inform significant positive effect to support the WHO recent recommendations for the wide use of bedaquiline.
Highlights • Age was examined in relation to CD4+ T-cell rise in HIV–tuberculosis (TB)-co-infected adults during combined antiretroviral therapy (cART). • Given cART, the age-related CD4+ T-cell ...recovery rate depended on sex and nutritional status. • Young age predicted CD4+ T-cell rise among women and normally nourished patients. • Optimal nutrition in TB–HIV-co-infected patients may enhance CD4+ T-cell recovery given cART.
ABSTRACT Using multivariate analyses, this study attempted to identify important traits explaining the relationship between milk production and quality produced by Holstein cows. Monthly milk records ...from three commercial dairy farms located in the Agreste region of Pernambuco, Brazil, collected in the period from 2007 to 2017, were used. A total of 5,872 observations regarding milk production, milk components and somatic cell score (SCS) were analyzed using principal component analysis (PCA) and cluster analysis. According to the former analysis, the first three principal components explained 79.69% of the total variation. Total solids content contributed 29.66% of the variation in the first principal component, while lactose content contributed 49.43% of the variation in the second principal component. According to the latter analysis, three clusters differed for all characteristics (p<0.001) and cluster 2 concentrated 43.15% (2,534) of the information with lower SCS and higher lactose content and milk production. Total solids, lactose and fat were considered the most representative traits explaining the variability of the data set. The multivariate techniques used in this study proved useful in obtaining effective characteristics, with three factors considered important in explaining the relationship between Holstein cows’ milk production and quality.
During the COVID-19 pandemic in 2020, a tuberculosis outbreak occurred in a university in eastern China, with 4,488 students and 421 staff on the campus. A 19-year-old student was diagnosed in August ...2019. Later, the first round of screening was initiated among close contacts, but no active cases were found. Till September 2020, four rounds of screening were performed. Four rounds of screening were conducted on September 9, November 8, November 22-25 in 2019 and September 2020, with 0, 5, 0 and 43 cases identified, respectively. A total of 66 active tuberculosis were found in the same university, including 4 sputum culture-positive and 7 sputum smear-positive. The total attack rate of active tuberculosis was 1.34% (66/4909). The whole-genome sequencing showed that the isolates belonged to the same L2 sub-specie and were sensitive to all tested antituberculosis drugs. Delay detection, diagnosis and report of cases were the major cause of this university tuberculosis epidemic. More attention should be paid to the asymptomatic students in the index class. After the occurrence of tuberculosis cases in schools, multiple rounds of screening should be carried out, and preventive therapy should be applied in a timely manner.
Background
Therapeutic strategies that induce effective neuroprotection and enhance intrinsic repair mechanisms are central goals for future treatment of multiple sclerosis (MS), as well as other ...diseases. Laquinimod (LQ) is an orally administered, central nervous system (CNS)‐active immunomodulator with demonstrated efficacy in MS clinical trials and a favorable safety and tolerability profile.
Aims
We aimed to explore the pathological, functional, and behavioral consequences of prophylactic and therapeutic (after presentation of peak clinical disease) LQ treatment in the chronic experimental autoimmune encephalomyelitis (EAE) mouse model of MS.
Materials and methods
Active EAE‐induced 8‐week‐old C57BL/6 mice were treated with 5 or 25 mg/kg/day LQ via oral gavage beginning on EAE post‐immunization day 0, 8, or 21. Clinical scores and rotorod motor performance were assessed throughout the disease course. Immune analysis of autoantigen‐stimulated splenocytes, electrophysiological conduction of callosal axons, and immunohistochemistry of white matter‐rich corpus callosum and spinal cord were performed.
Results
Prophylactic and therapeutic treatment with LQ significantly decreased mean clinical disease scores, inhibited Th1 cytokine production, and decreased the CNS inflammatory response. LQ‐induced improvement in axon myelination and integrity during EAE was functional, as evidenced by significant recovery of callosal axon conduction and axon refractoriness and pronounced improvement in rotorod motor performance. These improvements correlate with LQ‐induced attenuation of EAE‐induced demyelination and axon damage, and improved myelinated axon numbers.
Discussion
Even when initiated at peak disease, LQ treatment has beneficial effects within the chronic EAE mouse model. In addition to its immunomodulatory effects, the positive effects of LQ treatment on oligodendrocyte numbers and myelin density are indicative of significant, functional neuroprotective and neurorestorative effects.
Conclusions
Our results support a potential neuroprotective, in addition to immunomodulatory, effect of LQ treatment in inhibiting ongoing MS/EAE disease progression.
Consecutive sections immunostained with NF200 (green), MBP (red), and DAPI (blue) and imaged at 40x showed robust NF200 and MBP immunostaining in the anterior funiculus of normal controls and laquinimod pre‐ and post‐treated EAE groups. In contrast, sections from vehicle‐treated EAE mice had decreased myelin and axonal staining.
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